Methods for the synthesis of activated ethylfumarates and their use as intermediates

Patent metadata

Field	Value
Publication number	US-12202807-B2
Application number	US-202217972220-A
Country	US
Kind code	B2
Filing date	Oct 24, 2022
Priority date	Apr 27, 2012
Publication date	Jan 21, 2025
Grant date	Jan 21, 2025

Abstract

Disclosed embodiments relate to improved methods for the synthesis of activated fumarate intermediates and their use in chemical synthesis. Disclosed embodiments describe the synthesis of activated fumarate esters including those derived from activating groups including: 4-nitrophenyl, diphenylphophoryl azide, pivaloyl chloride, chlorosulfonyl isocyanate, p-nitrophenol, MEF, trifluoroacetyl and chlorine, for example, ethyl fumaroyl chloride and the subsequent use of the activated ester in situ. Further embodiments describe the improved synthesis of substituted aminoalkyl-diketopiperazines from unisolated and unpurified intermediates allowing for improved yields and reactor throughput.

First claim

What is claimed is:

1. A method of preparing a functionalized diketopiperazine comprising:
in a first reaction vessel, mixing monoethyl fumarate or an activated form thereof and at least one of diphenylphophoryl azide, pivaloyl chloride, chlorosulfonyl isocyanate, and trifluoroacetic anhydride in a first organic solvent to form a mixed anhydride;
in a second reaction vessel, combining the mixed anhydride, a second organic solvent, and an aminoalkyl-diketopiperazine according to the following formula (wherein n=1-7):

to form a functionalized diketopiperazine according to Formula I

and
quenching the reaction mixture with a third solvent.

2. The method of claim 1 wherein the aminoalkyl-diketopiperazine comprises a protecting group (PG) and the protecting group is removed from the aminoalkyl-diketopiperazine prior to reaction with the activated monoethyl fumarate.

3. The method of claim 2 , wherein the protecting group is trifluoroacetyl.

4. The method of claim 1 wherein the mixed anhydride is generated by reacting monoethyl fumaroyl chloride with pivalic acid.

5. The method of claim 1 further comprising saponification of the ethyl esters of the diketopiperazine of Formula I.

6. The method of claim 1 further comprising isolation of the activated derivative of monoethyl fumarate before reacting with the aminoalkyl-diketopiperazine.

7. The method of claim 1 , wherein a proton scavenger is added to the first reaction vessel.

8. The method of claim 7 , wherein the proton scavenger is an organic amine.

9. The method of claim 8 , wherein the organic amine is triethyl amine.

10. The method of claim 1 , further comprising cooling the first reaction vessel prior to addition of the monoethyl fumarate or an activated form thereof.

11. The method of claim 1 , wherein the first organic solvent is THF.

12. The method of claim 1 , wherein the second organic solvent is THF.

13. The method of claim 1 , comprising heating the second reaction vessel.

14. The method of claim 1 , wherein the third solvent is water.

15. A method of preparing a diketopiperazine of Formula I (n=1-7) comprising:

mixing 4-nitrophenol, an inorganic metallic base, and ethyl fumaryl chloride in a first organic solvent to produce a monoethyl fumarate ester;
combining the monoethylfumarate ester with an aminoalkyl-diketopiperazine having two primary amine functional groups and a proton scavenger in a second organic solvent; and mixing the combination for at least 1 hr.

16. The method of claim 15 , wherein the aminoalkyl-diketopiperazine having two primary amine functional groups is:

wherein n=1-7.

17. The method of claim 15 , wherein the first organic solvent is selected from acetone, acetonitrile, ethyl acetate, tetrahydrofuran, and dichloromethane.

18. The method of claim 15 wherein the proton scavenger is an inorganic base.

19. The method of claim 18 , wherein the inorganic base is selected from sodium hydroxide and sodium carbonate.

20. The method of claim 15 , wherein the combination is mixed for 1.5 to 18 hrs.

Assignees

• Mannkind Corp

Inventors

• Kraft Kelly Sullivan
• Freeman John J
• Serwinski Paul
• Pavia Vincent
• Phanstiel Otto
• Kaur Navneet

Classifications

• C07C67/30

  by modifying the acid moiety of the ester, such modification not being an introduction of an ester group · CPC title

• C07C67/39

  by oxidation of groups which are precursors for the acid moiety of the ester · CPC title

• C07C201/12

  by reactions not involving the formation of nitro groups · CPC title

• C07D241/08 Primary

  with oxygen atoms directly attached to ring carbon atoms · CPC title

• C07C205/43

  to carbon atoms of the same non-condensed six-membered aromatic ring or to carbon atoms of six-membered aromatic rings being part of the same condensed ring system · CPC title